Associations of antidepressants and antipsychotics with lipid parameters: Do CYP2D6/CYP2C19 genes play a role? A UK population-based study

Background Dyslipidaemia is an important risk factor for cardiovascular morbidity in people with severe mental illness and which contributes to premature mortality in this population. The link between antipsychotics and dyslipidaemia is well-established, whilst evidence on antidepressants is mixed. Aims To investigate (1) if antidepressant/antipsychotic use was associated with lipid parameters in UK Biobank participants, and (2) if CYP2D6 and CYP2C19 genetic variation plays a role. Methods Review of self-reported prescription medications identified participants taking antidepressants/antipsychotics. Total, low-, and high-density lipoprotein (L/HDL-C) cholesterol and triglycerides derived from blood samples. CYP2D6 and CYP2C19 metabolic phenotypes were assigned from genetic data. Linear regression investigated study aims. Results Of 469,739 participants, 36,043 took antidepressants and 3,255 antipsychotics. Significant associations were found between use of amitriptyline, fluoxetine, citalopram/escitalopram, sertraline, paroxetine, and venlafaxine with worse levels of each lipid parameter (i.e., higher total cholesterol, LDL-C, and triglycerides and lower HDL-C). Venlafaxine was associated with the worst lipid profile (total cholesterol, mean difference: 0·21 mmol/L, 95% confidence interval [CI]: 0·17 to 0·26, p <0·001). Antipsychotic use was associated with lower HDL-C and higher triglycerides (0·31 mmol/L, 95% CI 0·28 to 0·35, p <0·001). In participants taking sertraline, the CYP2C19 intermediate metaboliser phenotype was associated with higher HDL-C (0·05 mmol/L 95% CI: 0·01 to 0·09, p =0·007) and lower triglycerides (-0·17 mmol/L 95% CI: -0·29 to -0·05, p =0·007). Conclusions Antidepressants are significantly associated with adverse lipid profiles, potentially warranting baseline and regular monitoring of lipids. Further research should investigate why the CYP2C19 intermediate metaboliser phenotype may be protective for HDL-C and triglycerides in people taking sertraline. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement ARB is funded by the Wellcome Trust through a PhD Fellowship in Mental Health Science. This research was funded in whole or in part by the Wellcome Trust. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript (AAM) version arising from this submission. EB acknowledges the support of: Medical Research Council (G1100583, MR/W020238/1), National Institute of Health Research (NIHR200756), Mental Health Research UK - John Grace QC Scholarship 2018, Economic Social Research Councils Co-funded doctoral award, The British Medical Associations Margaret Temple Fellowship, Medical Research Council New Investigator and Centenary Awards (G0901310, G1100583), NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust and University College London. BW is funded by the China Scholarship Council-UCL Joint Research Scholarship. DPJO is supported by the University College London Hospitals NIHR Biomedical Research Centre and the NIHR North Thames Applied Research Collaboration. This funder had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The views expressed in this article are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: UK Biobank received ethical approval from the North West - Haydock Research Ethics Committee (reference: 21/NW/0157). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data used in this study is publicly available to authorised researchers via the UK Biobank.